Natural killer (NK) cells are a population of lymphocytes with defined characteristics that distinguish them from B or T lymphocytes. They have traditionally been considered to be non-specific killer cells for transformed or virus infected targets. However, more recently abundant evidence has accumulated to show that the cells mediate very specific lysis of non transformed cells. Furthermore, because NK cells do not rearrange T cell receptor or immunoglobulin genes this specificity must be mediated by a separate class of receptors that are also clonally distributed. Considerable evidence supporting this contention has been generated by participants of this program project. In addition to the ability to mediate cytotoxicity, recent evidence is also accumulating to show that NK cells exert a regulatory role for immune functions that are mediated via cytokines and not directly dependent on their ability to kill. The four components of this project will explore these varied aspects of NK cell biology. In the first Project,the gene for a cell surface molecule, 2B4, that is involved in the activation of the lytic function of all NK cells, will be inactivated by targeted deletion so that the function of the molecule can be delineated. In addition the ligand for this molecule will be identified. In the second project, the immune regulatory function of NK cells will be assessed utilizing the documented interactions between NK and B lymphocytes as a unique model system. In the third project the parameters regulating the acquisition of MHC class I receptors on NK cells will be studied. Finally, in the fourth project, tolerance induction to allogeneic bone marrow transplants will be studied both as a means to gain further insight into the mechanism of rejection and to attain a rational basis for the design of clinically applicable protocols. Although each of these projects are independent, they all have the same central research focus and are all highly interrelated, and can benefit from the program core.